Angiopoietin-like protein 8 (ANGPTL8) is an ANGPTL family member that has been implicated in both triglyceride and glucose metabolism. ANGPTL8 is also referred to in the literature as betatrophin, lipasin, TD26, RIFL (refeeding-induced fat and liver protein), and C19orf80. ANGPTL8 is produced by the liver and in white adipose tissue and circulates in the blood. ANGPTL8 is considered a mediator of post-prandial trafficking of fatty acids to adipose tissue and a regulator of postprandial glucose metabolism, but its mechanism of action remains unclear. Overexpression of ANGPTL8 has been associated with elevated triglyceride levels. (See, e.g., Santulli G, 2014, Frontiers in Endocrinology, 5:1-6; Zhang R and Abou-Samra A B, 2014, Cardiovascular Diabetology, 13:133).
Elevated blood triglyceride levels and hypertriglyceridemia are significant contributing factors to cardiovascular diseases. Elevated triglyceride levels can also be a sign of, and contributing factor to, conditions that increase a person's overall risk of heart disease, these conditions may include obesity, metabolic syndrome, excess body fat, high blood pressure, high blood sugar, and abnormal cholesterol levels. In addition, high triglyceride levels also contribute to decreased health status in subjects with poorly controlled type 2 diabetes, hypothyroidism, liver disease, kidney disease, and genetic metabolic disorders. Further complicating treatment for associated conditions, elevated triglyceride levels are a common side effect of routinely prescribed medications such as beta blockers, birth control, diuretics, steroids, and certain cancer treatments, such as tamoxifen.
Although there are therapeutics available that may reduce elevated triglyceride levels in a subject, there is a need for new agents that effectively reduce elevated triglyceride levels. In addition, there is a need for agents that may be used in methods of treatment for a variety of diseases and disorders associated with elevated triglycerides levels, high LDL-cholesterol levels, and/or low HDL-cholesterol levels.